tbuckley/cabot-search huggingface dataset:
Endpoints for clinical trials in ophthalmology
Authors: Leopold Schmetterer, Hendrik Scholl, Gerhard Garhöfer, Lucas Janeschitz-Kriegl, Federico Corvi, SriniVas R. Sadda, Felipe A. Medeiros
Journal: Progress in Retinal and Eye Research (2023)

With the identification of novel targets, the number of interventional clinical trials in ophthalmology has increased. Visual acuity has for a long time been considered the gold standard endpoint for clinical trials, but in the recent years it became evident that other endpoints are required for many indications including geographic atrophy and inherited retinal disease. In glaucoma the currently available drugs were approved based on their IOP lowering capacity. Some recent findings do, however, indicate that at the same level of IOP reduction, not all drugs have the same effect on visual field progression. For neuroprotection trials in glaucoma, novel surrogate endpoints are required, which may either include functional or structural parameters or a combination of both. A number of potential surrogate endpoints for ophthalmology clinical trials have been identified, but their validation is complicated and requires solid scientific evidence. In this article we summarize candidates for clinical endpoints in ophthalmology with a focus on retinal disease and glaucoma. Functional and structural biomarkers, as well as quality of life measures are discussed, and their potential to serve as endpoints in pivotal trials is critically evaluated.
Progressive transformation of the HIV-1 reservoir cell profile over two decades of antiviral therapy
Authors: Xiaodong Lian, Kyra W. Seiger, Elizabeth M. Parsons, Ce Gao, Weiwei Sun, Gregory T. Gladkov, Isabelle C. Roseto, Kevin B. Einkauf, Matthew R. Osborn, Joshua M. Chevalier, Chenyang Jiang, Jane Blackmer, Mary Carrington, Eric S. Rosenberg, Michael M. Lederman, Deborah K. McMahon, Ronald J. Bosch, Jeffrey M. Jacobson, Rajesh T. Gandhi, Michael J. Peluso, Tae-Wook Chun, Steven G. Deeks, Xu G. Yu, Mathias Lichterfeld
Journal: Cell Host & Microbe (2023)

HIV-1 establishes a life-long reservoir of virally infected cells which cannot be eliminated by antiretroviral therapy (ART). Here, we demonstrate a markedly altered viral reservoir profile of long-term ART-treated individuals, characterized by large clones of intact proviruses preferentially integrated in heterochromatin locations, most prominently in centromeric satellite/micro-satellite DNA. Longitudinal evaluations suggested that this specific reservoir configuration results from selection processes that promote the persistence of intact proviruses in repressive chromatin positions, while proviruses in permissive chromosomal locations are more likely to be eliminated. A bias toward chromosomal integration sites in heterochromatin locations was also observed for intact proviruses in study participants who maintained viral control after discontinuation of antiretroviral therapy. Together, these results raise the possibility that antiviral selection mechanisms during long-term ART may induce an HIV-1 reservoir structure with features of deep latency and, possibly, more limited abilities to drive rebound viremia upon treatment interruptions.
Enzymatic bionanocatalysts for combating peri-implant biofilm infections by specific heat-amplified chemodynamic therapy and innate immunomodulation
Authors: Zheng Su, Lingtong Kong, Jiawei Mei, Qianming Li, Zhengzheng Qian, Yuanyuan Ma, Yue Chen, Shenghong Ju, Jiaxing Wang, Weitao Jia, Chen Zhu, Wenpei Fan
Journal: Drug Resistance Updates (2023)
Zwitterionic betaines over HEPES as the new generation biocompatible pH buffers for cell culture
Authors: Peiming Liu, Jin Sun, Wan Peng, Yahui Gu, Xiaoxue Ji, Zhi Su, Pingsheng Liu, Jian Shen
Journal: Bioactive Materials (2023)

Good's buffers have been widely applied in cell/organ culture over the past half a century as biocompatible pH stabilizers. However, the emergence of severe adverse effects, such as cellular uptake, lysosomal autophagic activation, and visible light-induced cytotoxicity, raises serious questions over its biocompatibility while underlying mechanism was unclear. Here we report that riboflavin (RF, component of cell culture medium) generates 1O2, ·OH, and O2•- under visible light exposure during regular cell manipulation. These short half-life reactive oxygen species (ROS) react with tertiary amine groups of HEPES, producing 106.6 μM of H2O2. Orders of magnitude elevated half-life of ROS in the medium caused severe cytotoxicity and systematic disorder of normal cell functions. We have further designed and validated zwitterionic betaines as the new generation biocompatible organic pH buffers, which is able to completely avoid the adverse effects that found on HEPES and derivate Good's buffers. These findings may also open a new avenue for zwitterionic betaine based materials for biomedical applications.
Immune response differences in degradable and non-degradable alloy implants
Authors: Taravat Khodaei, Elizabeth Schmitzer, Abhirami P. Suresh, Abhinav P. Acharya
Journal: Bioactive Materials (2022)

Alloy based implants have made a great impact in the clinic and in preclinical research. Immune responses are one of the major causes of failure of these implants in the clinic. Although the immune responses toward non-degradable alloy implants are well documented, there is a poor understanding of the immune responses against degradable alloy implants. Recently, there have been several reports suggesting that degradable implants may develop substantial immune responses. This phenomenon needs to be further studied in detail to make the case for the degradable implants to be utilized in clinics. Herein, we review these new recent reports suggesting the role of innate and potentially adaptive immune cells in inducing immune responses against degradable implants. First, we discussed immune responses to allergen components of non-degradable implants to give a better overview on differences in the immune response between non-degradable and degradable implants. Furthermore, we also provide potential areas of research that can be undertaken that may shed light on the local and global immune responses that are generated in response to degradable implants.
Continuously released Zn2+ in 3D-printed PLGA/β-TCP/Zn scaffolds for bone defect repair by improving osteoinductive and anti-inflammatory properties
Authors: Chunxu Li, Fengbo Sun, Jingjing Tian, Jiahao Li, Haidan Sun, Yong Zhang, Shigong Guo, Yuanhua Lin, Xiaodan Sun, Yu Zhao
Journal: Bioactive Materials (2022)

Long-term nonunion of bone defects has always been a major problem in orthopedic treatment. Artificial bone graft materials such as Poly (lactic-co-glycolic acid)/β-tricalcium phosphate (PLGA/β-TCP) scaffolds are expected to solve this problem due to their suitable degradation rate and good osteoconductivity. However, insufficient mechanical properties, lack of osteoinductivity and infections after implanted limit its large-scale clinical application. Hence, we proposed a novel bone repair bioscaffold by adding zinc submicron particles to PLGA/β-TCP using low temperature rapid prototyping 3D printing technology. We first screened the scaffolds with 1 wt% Zn that had good biocompatibility and could stably release a safe dose of zinc ions within 16 weeks to ensure long-term non-toxicity. As designed, the scaffold had a multi-level porous structure of biomimetic cancellous bone, and the Young's modulus (63.41 ± 1.89 MPa) and compressive strength (2.887 ± 0.025 MPa) of the scaffold were close to those of cancellous bone. In addition, after a series of in vitro and in vivo experiments, the scaffolds proved to have no adverse effects on the viability of BMSCs and promoted their adhesion and osteogenic differentiation, as well as exhibiting higher osteogenic and anti-inflammatory properties than PLGA/β-TCP scaffold without zinc particles. We also found that this osteogenic and anti-inflammatory effect might be related to Wnt/β-catenin, P38 MAPK and NFkB pathways. This study lay a foundation for the follow-up study of bone regeneration mechanism of Zn-containing biomaterials. We envision that this scaffold may become a new strategy for clinical treatment of bone defects.
Double crosslinked biomimetic composite hydrogels containing topographical cues and WAY-316606 induce neural tissue regeneration and functional recovery after spinal cord injury
Authors: Xingchang Zhao, Xianzhe Lu, Kai Li, Shiqiang Song, Zhaohui Luo, Chuanchuan Zheng, Chengliang Yang, Xiumei Wang, Liqiang Wang, Yujin Tang, Chong Wang, Jia Liu
Journal: Bioactive Materials (2022)

Spinal cord injury (SCI) is an overwhelming and incurable disabling condition, for which increasing forms of multifunctional biomaterials are being tested, but with limited progression. The promising material should be able to fill SCI-induced cavities and direct the growth of new neurons, with effective drug loading to improve the local micro-organism environment and promote neural tissue regeneration. In this study, a double crosslinked biomimetic composite hydrogel comprised of acellularized spinal cord matrix (ASCM) and gelatin-acrylated-β-cyclodextrin-polyethene glycol diacrylate (designated G-CD-PEGDA) hydrogel, loaded with WAY-316606 to activate canonical Wnt/β-catenin signaling, and reinforced by a bundle of three-dimensionally printed aligned polycaprolactone (PCL) microfibers, was constructed. The G-CD-PEGDA component endowed the composite hydrogel with a dynamic structure with a self-healing capability which enabled cell migration, while the ASCM component promoted neural cell affinity and proliferation. The diffusion of WAY-316606 could recruit endogenous neural stem cells and improve neuronal differentiation. The aligned PCL microfibers guided neurite elongation in the longitudinal direction. Animal behavior studies further showed that the composite hydrogel could significantly recover the motor function of rats after SCI. This study provides a proficient approach to produce a multifunctional system with desirable physiological, chemical, and topographical cues for treating patients with SCI.
SAXS imaging reveals optimized osseointegration properties of bioengineered oriented 3D-PLGA/aCaP scaffolds in a critical size bone defect model
Authors: Elisa A. Casanova, Adrian Rodriguez-Palomo, Lisa Stähli, Kevin Arnke, Olivier Gröninger, Melanie Generali, Yvonne Neldner, Simon Tiziani, Ana Perez Dominguez, Manuel Guizar-Sicairos, Zirui Gao, Christian Appel, Leonard C. Nielsen, Marios Georgiadis, Franz E. Weber, Wendelin Stark, Hans-Christoph Pape, Paolo Cinelli, Marianne Liebi
Journal: Biomaterials (2023)

Healing large bone defects remains challenging in orthopedic surgery and is often associated with poor outcomes and complications. A major issue with bioengineered constructs is achieving a continuous interface between host bone and graft to enhance biological processes and mechanical stability. In this study, we have developed a new bioengineering strategy to produce oriented biocompatible 3D PLGA/aCaP nanocomposites with enhanced osseointegration. Decellularized scaffolds -containing only extracellular matrix- or scaffolds seeded with adipose-derived mesenchymal stromal cells were tested in a mouse model for critical size bone defects. In parallel to micro-CT analysis, SAXS tensor tomography and 2D scanning SAXS were employed to determine the 3D arrangement and nanostructure within the critical-sized bone. Both newly developed scaffold types, seeded with cells or decellularized, showed high osseointegration, higher bone quality, increased alignment of collagen fibers and optimal alignment and size of hydroxyapatite minerals.
Outcome of limited‐stage peripheral <scp>T‐Cell</scp> lymphoma after <scp>CHOP</scp>(−like) therapy: A population based study of 239 patients from the Nordic lymphoma epidemiology group
Authors: Ahmed Ludvigsen Al‐Mashhadi, Henrik Cederleuf, Rasmus Kuhr Jensen, Torsten Holm Nielsen, Martin Bjerregård Pedersen, Thomas Bech Mortensen, Thomas Relander, Mats Jerkeman, Anne Ortved Gang, Anne Louise Kristensen, Michael Roost Clausen, Peter de Nully Brown, Marianne Tang Severinsen, Lasse Hjort Jakobsen, Fredrik Ellin, Tarec Christoffer El‐Galaly
Journal: American Journal of Hematology (2023)

Abstract Peripheral T‐Cell Lymphomas (PTCLs) are rare, aggressive lymphomas with poor outcomes, but limited‐stage disease is infrequent and not well‐described. This study reports outcomes and prognostic factors in limited‐stage nodal PTCLs in a binational population‐based setting. Patients were identified from the Danish and Swedish lymphoma registries. Adults diagnosed with limited‐stage nodal PTCL (stage I‐II) and treated with CHOP(−like) therapy ±radiotherapy between 2000 and 2014 were included. Medical records were reviewed by local investigators. A total of 239 patients with a median age of 62 years were included; 67% received 6–8 cycles of CHOP(−like) therapy and 22% received 3–4 cycles, of which 59% also received radiotherapy. Autologous stem cell transplant consolidation was administered to 16% of all patients. Median follow‐up was 127 months with 5‐years overall survival (OS) of 58% (95% CI: 53–65) and progression‐free survival (PFS) of 53% (95% CI: 47–59). In multivariable analysis, age ≥ 60 years and B‐symptoms were unfavorable and ALK+ anaplastic large cell T‐Cell lymphoma was favorable for survival outcomes. There was no difference in treatment‐specific outcome (3–4 cycles vs. 6–8 cycles of CHOP(−like) ± radiotherapy). Low‐risk patients (age &lt; 60 without B‐symptoms) had a 5‐year OS of 77% (95% CI 67–89%). In the present study of limited‐stage nodal PTCL, survival after curative intent chemotherapy +/− radiotherapy was inferior to that of limited‐stage diffuse large B‐cell lymphoma, but a subgroup of young patients without B‐symptoms had very good outcomes. Treatment outcomes after 3–4 cycles versus 6–8 cycles of CHOP(−like) therapy were comparable.
Spatiotemporal Regulation of the Bone Immune Microenvironment via Dam‐Like Biphasic Bionic Periosteum for Bone Regeneration (Adv. Healthcare Mater. 1/2023)
Authors: Zonghan Xu, Liang Wu, Yu Tang, Kun Xi, Jincheng Tang, Yichang Xu, Jingzhi Xu, Jian Lu, Kaijin Guo, Yong Gu, Liang Chen
Journal: Advanced Healthcare Materials (2023)
Oxygen metabolism-balanced engineered hydrogel microspheres promote the regeneration of the nucleus pulposus by inhibiting acid-sensitive complexes
Authors: Ziang Li, Feng Cai, Jincheng Tang, Yichang Xu, Kaijin Guo, Zonghan Xu, Yu Feng, Kun Xi, Yong Gu, Liang Chen
Journal: Bioactive Materials (2022)

Intervertebral disc degeneration (IVDD) is commonly caused by imbalanced oxygen metabolism-triggered inflammation. Overcoming the shortcomings of antioxidants in IVDD treatment, including instability and the lack of targeting, remains challenging. Microfluidic and surface modification technologies were combined to graft chitosan nanoparticles encapsulated with strong reductive black phosphorus quantum dots (BPQDs) onto GelMA microspheres via amide bonds to construct oxygen metabolism-balanced engineered hydrogel microspheres (GM@CS-BP), which attenuate extracellular acidosis in nucleus pulposus (NP), block the inflammatory cascade, reduce matrix metalloproteinase expression (MMP), and remodel the extracellular matrix (ECM) in intervertebral discs (IVDs). The GM@CS-BP microspheres reduce H2O2 intensity by 229%. Chemical grafting and electrostatic attraction increase the encapsulation rate of BPQDs by 167% and maintain stable release for 21 days, demonstrating the antioxidant properties and sustained modulation of the BPQDs. After the GM@CS-BP treatment, western blotting revealed decreased acid-sensitive ion channel-3 and inflammatory factors. Histological staining in an 8-week IVDD model confirmed the regeneration of NP. GM@CS-BP microspheres therefore maintain a balance between ECM synthesis and degradation by regulating the positive feedback between imbalanced oxygen metabolism in IVDs and inflammation. This study provides an in-depth interpretation of the mechanisms underlying the antioxidation of BPQDs and a new approach for IVDD treatment.
Advances in the clinical management of uveal melanoma
Authors: Richard D. Carvajal, Joseph J. Sacco, Martine J. Jager, David J. Eschelman, Roger Olofsson Bagge, J. William Harbour, Nicholas D. Chieng, Sapna P. Patel, Anthony M. Joshua, Sophie Piperno-Neumann
Journal: Nature Reviews Clinical Oncology (2023)
Association of Appropriate Empirical Antimicrobial Therapy With In-Hospital Mortality in Patients With Bloodstream Infections in the US
Authors: Tetsu Ohnuma, Shingo Chihara, Blair Costin, Miriam M. Treggiari, Raquel R. Bartz, Karthik Raghunathan, Vijay Krishnamoorthy
Journal: JAMA Network Open (2023)

Bloodstream infections (BSIs) are a major public health problem associated with high morbidity. Little evidence exists regarding the epidemiology of BSIs and the use of appropriate empirical antimicrobial therapy.To estimate the association between receipt of appropriate initial empirical antimicrobial therapy and in-hospital mortality.This retrospective cross-sectional study used data from the Premier Healthcare database from 2016 to 2020. The analysis included 32 100 adult patients (aged ≥18 years) with BSIs from 183 US hospitals who received at least 1 new systemic antimicrobial agent within 2 days after blood samples were collected during the hospitalization. Patients with polymicrobial infections were excluded from the analysis.Appropriate empirical therapy was defined as initiation of at least 1 new empirical antimicrobial agent to which the pathogen isolated from blood culture was susceptible either on the day of or the day after the blood sample was collected.Multilevel logistic regression models were used to estimate the association between receipt of appropriate initial empirical antimicrobial therapy and in-hospital mortality for patients infected with gram-negative rods (GNRs), gram-positive cocci (GPC), and Candida species.Among 32 100 patients who had BSIs and received new empirical antimicrobial agents, the mean (SD) age was 64 (16) years; 54.8% were male, 69.9% were non-Hispanic White, and in-hospital mortality was 14.3%. The most common pathogens were Escherichia coli (58.4%) and Staphylococcus aureus (31.8%). Among patients infected with S aureus, methicillin-resistant S aureus was isolated in 43.6%. The crude proportions of appropriate empirical therapy use were 94.4% for GNR, 97.0% for GPC, and 65.1% for Candida species. The proportions of appropriate therapy use for resistant organisms were 55.3% for carbapenem-resistant Enterobacterales species and 60.4% for vancomycin-resistant Enterococcus species. Compared with inappropriate empirical therapy, receipt of appropriate empirical antimicrobial therapy was associated with lower in-hospital risk of death for 3 pathogen groups (GNR: adjusted odds ratio [aOR], 0.52 [95% CI, 0.42-0.64]; GPC: aOR, 0.60 [95% CI, 0.47-0.78]; Candida species: aOR, 0.43 [95% CI, 0.21-0.87]).In this cross-sectional study of patients hospitalized with BSIs, receipt of appropriate initial empirical antimicrobial therapy was associated with lower in-hospital mortality. It is important for clinicians to carefully choose empirical antimicrobial agents to improve outcomes in patients with BSIs.
Characteristics and Outcomes for Hospitalized Patients With Cutaneous T-Cell Lymphoma
Authors: George Glinos, Grace Wei, Jacob Nosewicz, Farah Abdulla, Pei-Ling Chen, Catherine Chung, Benjamin H. Kaffenberger, Christiane Querfeld, Michi M. Shinohara, Lubomir Sokol, Jasmine Zain, Ambuj Kumar, Lucia Seminario-Vidal
Journal: JAMA Dermatology (2023)

Cutaneous T-cell lymphoma (CTCL) is a group of rare, complex cutaneous malignant neoplasms associated with significant disease burden on patients and the health care system. Currently, the population of patients with CTCL admitted to the hospital remains largely uncharacterized and poorly understood.
Development of a Machine Learning Model for Sonographic Assessment of Gestational Age
Authors: Chace Lee, Angelica Willis, Christina Chen, Marcin Sieniek, Amber Watters, Bethany Stetson, Akib Uddin, Jonny Wong, Rory Pilgrim, Katherine Chou, Daniel Tse, Shravya Shetty, Ryan G. Gomes
Journal: JAMA Network Open (2023)

Fetal ultrasonography is essential for confirmation of gestational age (GA), and accurate GA assessment is important for providing appropriate care throughout pregnancy and for identifying complications, including fetal growth disorders. Derivation of GA from manual fetal biometry measurements (ie, head, abdomen, and femur) is operator dependent and time-consuming.
Social Work Staffing and Use of Palliative Care Among Recently Hospitalized Veterans
Authors: Portia Y. Cornell, Christopher W. Halladay, Anna-Rae Montano, Caitlin Celardo, Gina Chmelka, Jennifer W. Silva, James L. Rudolph
Journal: JAMA Network Open (2023)

Palliative care improves quality of life for patients and families but may be underused. To assess the association of an intervention to increase social work staffing in Veterans Health Administration primary care teams with use of palliative care among veterans with a recent hospitalization. This cohort study used differences-in-differences analyses of the change in palliative care use associated with implementation of the Social Work Patient Aligned Care Team (PACT) staffing program, conducted from October 1, 2016, to September 30, 2019. The study included 71 VA primary care sites serving rural veterans. Participants were adult veterans who received primary care services from a site enrolled in the program and who received inpatient hospital care. Data were analyzed from January 2020 to August 2022. The PACT staffing program was a clinic-level intervention that provided 3-year seed funding to Veterans Health Administration medical centers to hire 1 or more additional social workers in primary care teams. Staggered timing of the intervention enabled comparison of mean outcomes across sites before and after the intervention. The primary outcome was the number of individuals per 1000 veterans who had any palliative care use in 30 days after an inpatient hospital stay. The analytic sample included 43 200 veterans (mean [SD] age, 65.34 [13.95] years; 37 259 [86.25%] men) and a total of 91 675 episodes of inpatient hospital care. Among the total cohort, 8611 veterans (9.39%) were Black, 77 069 veterans (84.07%) were White, and 2679 veterans (2.92%) were another race (including American Indian or Alaskan Native, Asian, and Native Hawaiian or other Pacific Islander). A mean of 14.5 individuals per 1000 veterans (1329 individuals in all) used palliative care after a hospital stay. After the intervention, there was an increase of 15.6 (95% CI, 9.2-22.3) individuals per 1000 veterans using palliative or hospice care after a hospital stay, controlling for national time trends and veteran characteristics-a 2-fold difference relative to the mean. This cohort study found significant increases in use of palliative care for recently hospitalized veterans whose primary care team had additional social work staffing. These findings suggest that social workers may increase access to and/or use of palliative care. Future work should assess the mechanism for this association and whether the increase in palliative care is associated with other health or health care outcomes.
Comorbidities of Keloid and Hypertrophic Scars Among Participants in UK Biobank
Authors: Chuin Y. Ung, Alasdair Warwick, Alexandros Onoufriadis, Jonathan N. Barker, Maddy Parsons, John A. McGrath, Tanya J. Shaw, Nick Dand
Journal: JAMA Dermatology (2023)

Keloids and hypertrophic scars (excessive scarring) are relatively understudied disfiguring chronic skin conditions with high treatment resistance.
Generalized, Linear Hyperkeratotic Papules With Numerous White Spicules and Comedo-like Plugs
Authors: Tian Chen, Dong-Lai Ma
Journal: JAMA Dermatology (2023)

A school-aged boy presents with generalized, linear hyperkeratotic papules with numerous central small filiform keratotic white spicules and brown plugs on the head, face, neck, trunk, and bilateral upper and lower extremities. What is your diagnosis?